Muscular dystrophies (MD) are defined as a group of inherited muscle disorders characterized by the progressive degeneration and weakness of voluntary skeletal muscle (Davies and Nowak, 2006). The various forms of MD vary widely with respect to age of onset, incidence, pattern of inheritance, rate of progression, and distribution and severity of muscle weakness. Certain muscular dystrophies can involve cardiac and smooth muscle tissue. MD most commonly exhibits an X-recessive mode of transmission, and is usually caused by mutations in the DMD gene on Xp21.2. Resulting in deficiencies in dystrophin protein, DMD mutations cause rapidly progressive weakness and wasting of the proximal muscles in the lower body. Duchenne MD (DMD), the most common neuromuscular disorder, is caused by frameshift mutations that result in the complete absence of functional dystrophin, whereas the phenotypically less severe Becker's MD is associated with missense and inframe deletions that result in reduced levels of functional dystrophin or expression of partially functional protein (Davies and Nowak, 2006). This structural protein functions to link the actin cytoskeleton with muscle fibre membranes across the sarcolemma, providing structural support to the muscle cell (Ervasti, 2007). The absence of dystrophin compromises the complex across the muscle, leading to degeneration of muscle tissue. Affecting 1 in 4,000 live male births, DMD is correlated with onset before age 6 and a typical life span of 20-25 years; in contrast, Becker's MD has onset in adolescence or adulthood with symptoms similar to but generally less severe than DMD. These include muscle pseudohypertrophy, proximal muscle atrophy, and rarely, cardiomyopathy and/or mental deficits.
Emery-Dreifuss MD (EDMD) is another form of late onset X-recessive MD caused by deficiencies in the emerin protein, encoded by the EMD gene on Xq28 (Ellis, 2006). EDMD is phenotypically distinct from other X-linked MDs in that there is humeroperoneal distribution of muscle wasting, absence of muscle pseudohypertrophy, and at very high frequency, cardiomyopathy.
There is a need in the art to identify Four and a Half LIM domains protein 1 (FHL-1) mutations, and the proteins encoded therefrom that are associated with muscular myopathies including muscular dystrophy and cardiomyopathy. LIM domains, named after their initial discovery in the proteins Lin11, Isl-1 & Mec-3, are protein structural domains, composed of two contiguous zinc finger domains, separated by a two-amino acid residue hydrophobic linker. Further there is a need in the art to be able to screen for such mutations to identify individuals that have or are at risk for developing muscular myopathies, including muscular dystrophy and cardiomyopathy.